Assistant Professor of Neurology, of Neurosurgery and of Bioengineering and, by courtesy, of Electrical Engineering

Neurology & Neurological Sciences

Bio

Bio

The Lee Lab uses interdisciplinary approaches from biology and engineering to analyze, debug, and manipulate systems-level brain circuits. We seek to understand the connectivity and function of these large-scale networks in order to drive the development of new therapies for neurological diseases. This research finds its basic building blocks in areas ranging from medical imaging and signal processing to genetics and molecular biology.

Dr. Lee is a recipient of the 2010 NIH/NIBIB R00 Award, the 2010 NIH Director's New Innovator Award, the 2010 Okawa Foundation Research Grant Award, the 2011 NSF CAREER Award, the 2012 Alfred P. Sloan Foundation Research Fellowship Award, and the 2013 Alzheimer's Association New Investigator Award.

Abstract

In preclinical studies, implanted electrodes can cause severe degradation of MRI images and hence are seldom used for chronic studies employing functional magnetic resonance imaging. In this study, we developed carbon fiber optrodes (optical fiber and electrode hybrid devices), which can be utilised in chronic longitudinal studies aiming to take advantage of emerging optogenetic technologies, and compared them with the more widely used tungsten optrodes. We find that optrodes constructed using small diameter (~130 μm) carbon fiber electrodes cause significantly reduced artifact on functional MRI images compared to those made with 50 μm diameter tungsten wire and at the same time the carbon electrodes have lower impedance, which leads to higher quality LFP recordings. In order to validate this approach, we use these devices to study optogenetically-induced seizure-like afterdischarges in rats sedated with dexmedetomidine and compare these to sub (seizure) threshold stimulations in the same animals. The results indicate that seizure-like afterdischarges involve several extrahippocampal brain regions that are not recruited by subthreshold optogenetic stimulation of the hippocampus at 20 Hz. Subthreshold stimulation led to activation of the entire ipsilateral hippocampus and septum, whereas afterdischarges additionally produced activations in the contralateral hippocampal formation, neocortex, cerebellum, nucleus accumbens, and thalamus. Although we demonstrate just one application, given the ease of fabrication, we anticipate that carbon fiber optrodes could be utilised in a variety of studies that could benefit from longitudinal optogenetic functional magnetic resonance imaging.

Abstract

Despite the potential of stem cell-derived neural transplants for treating intractable neurological diseases, the global effects of a transplant's electrical activity on host circuitry have never been measured directly, preventing the systematic optimization of such therapies. Here, we overcome this problem by combining optogenetics, stem cell biology, and neuroimaging to directly map stem cell-driven neural circuit formation in vivo. We engineered human induced pluripotent stem cells (iPSCs) to express channelrhodopsin-2 and transplanted resulting neurons to striatum of rats. To non-invasively visualize the function of newly formed circuits, we performed high-field functional magnetic resonance imaging (fMRI) during selective stimulation of transplanted cells. fMRI successfully detected local and remote neural activity, enabling the global graft-host neural circuit function to be assessed. These results demonstrate the potential of a novel neuroimaging-based platform that can be used to identify how a graft's electrical activity influences the brain network in vivo.

Abstract

Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures.

Abstract

In vivo imaging is increasingly being utilized in studies investigating stem cell-based treatments for neurological disorders. Direct labeling is used in preclinical and clinical studies to track the fate of transplanted cells. To further determine cell viability, experimental studies are able to take advantage of reporter gene technologies. Structural and functional brain imaging can also be used alongside cell imaging as biomarkers of treatment efficacy. Furthermore, it is possible that new imaging techniques could be used to monitor functional integration of stem cell-derived cells with the host nervous system. In this review, we examine recent developments in these areas and identify promising directions for future research at the interface of stem cell therapies and neuroimaging.

Abstract

Optogenetic functional magnetic resonance imaging (of MRI) technology enables cell-type-specific, temporally precise neuronal control and the accurate, in vivo readout of the resulting activity across the entire brain. With the ability to precisely control excitation and inhibition parameters and accurately record the resulting activity, there is an increased need for a high-throughput method to bring the of MRI studies to their full potential. In this paper, an advanced system facilitating real-time fMRI with interactive control and analysis in a fraction of the MRI acquisition repetition time (TR) is proposed. With high-processing speed, sufficient time will be available for the integration of future developments that further enhance of MRI data or streamline the study. We designed and implemented a highly optimised, massively parallel system using graphics processing units (GPUs), which achieves the reconstruction, motion correction, and analysis of 3D volume data in approximately 12.80 ms. As a result, with a 750 ms TR and 4 interleaf fMRI acquisition, we can now conduct sliding window reconstruction, motion correction, analysis and display in approximately 1.7% of the TR. Therefore, a significant amount of time can now be allocated to integrating advanced but computationally intensive methods that improve image quality and enhance the analysis results within a TR. Utilising the proposed high-throughput imaging platform with sliding window reconstruction, we were also able to observe the much-debated initial dips in our of MRI data. Combined with methods to further improve SNR, the proposed system will enable efficient real-time, interactive, high-throughput of MRI studies.

Abstract

Optogenetic functional magnetic resonance imaging (ofMRI) is a novel approach that combines optogenetic control of neural circuits with high-field functional MRI. Optogenetics is a neuro-modulation technology in which light-activated trans-membrane conductance regulators are introduced into specifically targeted cell types to allow temporally precise, millisecond-scale activity modulation in vivo. By combining optogenetic control with fMRI readout, neural activity arising from specific circuit elements defined by genetic identity, cell body location, and axonal projection targets can be monitored in vivo across the whole brain. These unique features of ofMRI open new vistas for in vivo characterization of the dense plexus of neural connections according to their type and functionality.

Abstract

To evaluate two methods of scanning and tissue processing to achieve accurate magnetic resonance (MR)-histologic correlation in human prostate specimens.Two prostates had acrylic paint markers injected to define the plane of imaging and serve as internal fiducials. Each was placed on a polycarbonate plane-finder device (PFD), which was adjusted to align the imaging and cutting planes. Three prostates were aligned by use of a plane finder key (PFK), a polycarbonate plate that locks the specimen in a cylindrical carrier. Markers were injected for registration analysis. Prostates were imaged, then sectioned. Imaging software was used to create registration maps of the MR and histology images. Measurements between control points were made and compared.Accurate correlation was achieved between MR and histologic images. The mean displacement (MD) between the corresponding registration points using the PFD technique ranged from 1.11-1.38 mm for each section. The MD for all sections was 1.24 mm. The MD using the PFK technique ranged from 0.79-1.01 mm for each section, and the MD across all sections for the PFK was 0.92 mm.We describe two methods that can achieve accurate, reproducible correlation between MR imaging and histologic sections in human prostatectomy specimens.

Abstract

Optimizing the diffusion-weighted imaging (DWI) parameters (i.e., the b-value and the number of image averages) to the tissue of interest is essential for producing high-quality apparent diffusion coefficient (ADC) maps. Previous investigation of this optimization was performed assuming Gaussian noise statistics for the ADC map, which is only valid for high signal-to-noise ratio (SNR) imaging. In this work, the true statistics of the noise in ADC maps are derived, followed by an optimization of the DWI parameters as a function of the imaging SNR. Specifically, it is demonstrated that the optimum b-value is a monotonically increasing function of the imaging SNR, which converges to the optimum b-value from previously proposed approaches for high-SNR cases, while exhibiting a significant deviation from this asymptote for low-SNR situations. Incorporating the effects of T(2) weighting further increases the SNR dependence of the optimal parameters. The proposed optimization scheme is particularly important for high-resolution DWI, which intrinsically suffers from low SNR and therefore cannot afford the use of the conventional high b-values. Comparison scans were performed for high-resolution DWI of the spinal cord, demonstrating the improvements in the resulting images and the ADC maps achieved by this method.

Abstract

Despite the overwhelming need, there has been a relatively large gap in our ability to trace network level activity across the brain. The complex dense wiring of the brain makes it extremely challenging to understand cell-type specific activity and their communication beyond a few synapses. Recent development of the optogenetic functional magnetic resonance imaging (ofMRI) provides a new impetus for the study of brain circuits by enabling causal tracing of activities arising from defined cell types and firing patterns across the whole brain. Brain circuit elements can be selectively triggered based on their genetic identity, cell body location, and/or their axonal projection target with temporal precision while the resulting network response is monitored non-invasively with unprecedented spatial and temporal accuracy. With further studies including technological innovations to bring ofMRI to its full potential, ofMRI is expected to play an important role in our system-level understanding of the brain circuit mechanism.

Abstract

Despite a rapidly-growing scientific and clinical brain imaging literature based on functional magnetic resonance imaging (fMRI) using blood oxygenation level-dependent (BOLD) signals, it remains controversial whether BOLD signals in a particular region can be caused by activation of local excitatory neurons. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications. Using a novel integrated technology unifying optogenetic control of inputs with high-field fMRI signal readouts, we show here that specific stimulation of local CaMKIIalpha-expressing excitatory neurons, either in the neocortex or thalamus, elicits positive BOLD signals at the stimulus location with classical kinetics. We also show that optogenetic fMRI (of MRI) allows visualization of the causal effects of specific cell types defined not only by genetic identity and cell body location, but also by axonal projection target. Finally, we show that of MRI within the living and intact mammalian brain reveals BOLD signals in downstream targets distant from the stimulus, indicating that this approach can be used to map the global effects of controlling a local cell population. In this respect, unlike both conventional fMRI studies based on correlations and fMRI with electrical stimulation that will also directly drive afferent and nearby axons, this of MRI approach provides causal information about the global circuits recruited by defined local neuronal activity patterns. Together these findings provide an empirical foundation for the widely-used fMRI BOLD signal, and the features of of MRI define a potent tool that may be suitable for functional circuit analysis as well as global phenotyping of dysfunctional circuitry.

Abstract

FeCo-graphitic carbon shell nanocrystals are a novel MRI contrast agent with unprecedented high per-metal-atom-basis relaxivity (r(1) = 97 mM(-1) sec(-1), r(2) = 400 mM(-1) sec(-1)) and multifunctional capabilities. While the conventional gadolinium-based contrast-enhanced angiographic magnetic MRI has proven useful for diagnosis of vascular diseases, its short circulation time and relatively low sensitivity render high-resolution MRI of morphologically small vascular structures such as those involved in collateral, arteriogenic, and angiogenic vessel formation challenging. Here, by combining FeCo-graphitic carbon shell nanocrystals with high-resolution MRI technique, we demonstrate that such microvessels down to approximately 100 mum can be monitored in high contrast and noninvasively using a conventional 1.5-T clinical MRI system, achieving a diagnostic imaging standard approximating that of the more invasive X-ray angiography. Preliminary in vitro and in vivo toxicity study results also show no sign of toxicity.

Abstract

Flow-independent angiography is a non-contrast-enhanced technique that can generate vessel contrast even with reduced blood flow in the lower extremities. A method is presented for producing these angiograms with magnetization-prepared balanced steady-state free precession (bSSFP). Because bSSFP yields bright fat signal, robust fat suppression is essential for detailed depiction of the vasculature. Therefore, several strategies have been investigated to improve the reliability of fat suppression within short scan times. Phase-sensitive SSFP can efficiently suppress fat; however, partial volume effects due to fat and water occupying the same voxel can lead to the loss of blood signal. In contrast, alternating repetition time (ATR) SSFP minimizes this loss; however, the level of suppression is compromised by field inhomogeneity. Finally, a new double-acquisition ATR-SSFP technique reduces this sensitivity to off-resonance. In vivo results indicate that the two ATR-based techniques provide more reliable contrast when partial volume effects are significant.

Abstract

The concentric rings two-dimensional (2D) k-space trajectory enables flexible trade-offs between image contrast, signal-to-noise ratio (SNR), spatial resolution, and scan time. However, to realize these benefits for in vivo imaging applications, a robust method is desired to deal with fat signal in the acquired data. Multipoint Dixon techniques have been shown to achieve uniform fat suppression with high SNR-efficiency for Cartesian imaging, but application of these methods for non-Cartesian imaging is complicated by the fact that fat off-resonance creates significant blurring artifacts in the reconstruction. In this work, two fat-water separation algorithms are developed for the concentric rings. A retracing design is used to sample rings near the center of k-space through multiple revolutions to characterize the fat-water phase evolution difference at multiple time points. This acquisition design is first used for multipoint Dixon reconstruction, and then extended to a spectroscopic approach to account for the trajectory's full evolution through 3D k-t space. As the trajectory is resolved in time, off-resonance effects cause shifts in frequency instead of spatial blurring in 2D k-space. The spectral information can be used to assess field variation and perform robust fat-water separation. In vivo experimental results demonstrate the effectiveness of both algorithms.

Abstract

Single-shot echo-planar imaging (ss-EPI) has not been used widely for diffusion-weighted imaging (DWI) of the spinal cord, because of the magnetic field inhomogeneities around the spine, the small cross-sectional size of the spinal cord, and the increased motion in that area due to breathing, swallowing, and cerebrospinal fluid (CSF) pulsation. These result in artifacts with the usually long readout duration of the ss-EPI method. Reduced field-of-view (FOV) methods decrease the required readout duration for ss-EPI, thereby enabling its practical application to imaging of the spine. In this work, a reduced FOV single-shot diffusion-weighted echo-planar imaging (ss-DWEPI) method is proposed, in which a 2D spatially selective echo-planar RF excitation pulse and a 180 degrees refocusing pulse reduce the FOV in the phase-encode (PE) direction, while suppressing the signal from fat simultaneously. With this method, multi slice images with higher in-plane resolutions (0.94 x 0.94 mm(2) for sagittal and 0.62 x 0.62 mm(2) for axial images) are achieved at 1.5 T, without the need for a longer readout.

Abstract

Passband balanced-steady-state free precession (b-SSFP) fMRI is a recently developed method that utilizes the passband (flat portion) of the b-SSFP off-resonance response to measure MR signal changes elicited by changes in tissue oxygenation following increases in neuronal activity. Rapid refocusing and short readout durations of b-SSFP, combined with the relatively large flat portion of the b-SSFP off-resonance spectrum allows distortion-free full-brain coverage with only two acquisitions. This allows for high-resolution functional imaging, without the spatial distortion frequently encountered in conventional high-resolution functional images. Finally, the 3D imaging compatibility of the b-SSFP acquisitions permits isotropic-voxel-size high-resolution acquisitions. In this study we address some of the major technical issues involved in obtaining passband b-SSFP-based functional brain images with practical imaging parameters and demonstrate the advantages through breath-holding and visual field mapping experiments.

Abstract

The concentric rings two-dimensional (2D) k-space trajectory provides an alternative way to sample polar data. By collecting 2D k-space data in a series of rings, many unique properties are observed. The concentric rings are inherently centric-ordered, provide a smooth weighting in k-space, and enable shorter total scan times. Due to these properties, the concentric rings are well-suited as a readout trajectory for magnetization-prepared studies. When non-Cartesian trajectories are used for MRI, off-resonance effects can cause blurring and degrade the image quality. For the concentric rings, off-resonance blur can be corrected by retracing rings near the center of k-space to obtain a field map with no extra excitations, and then employing multifrequency reconstruction. Simulations show that the concentric rings exhibit minimal effects due to T(2) (*) modulation, enable shorter scan times for a Nyquist-sampled dataset than projection-reconstruction imaging or Cartesian 2D Fourier transform (2DFT) imaging, and have more spatially distributed flow and motion properties than Cartesian sampling. Experimental results show that off-resonance blurring can be successfully corrected to obtain high-resolution images. Results also show that concentric rings effectively capture the intended contrast in a magnetization-prepared sequence.

Abstract

The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2? (reciprocal of T2? relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.

Abstract

Nanocrystals with advanced magnetic or optical properties have been actively pursued for potential biological applications, including integrated imaging, diagnosis and therapy. Among various magnetic nanocrystals, FeCo has superior magnetic properties, but it has yet to be explored owing to the problems of easy oxidation and potential toxicity. Previously, FeCo nanocrystals with multilayered graphitic carbon, pyrolytic carbon or inert metals have been obtained, but not in the single-shelled, discrete, chemically functionalized and water-soluble forms desired for biological applications. Here, we present a scalable chemical vapour deposition method to synthesize FeCo/single-graphitic-shell nanocrystals that are soluble and stable in water solutions. We explore the multiple functionalities of these core-shell materials by characterizing the magnetic properties of the FeCo core and near-infrared optical absorbance of the single-layered graphitic shell. The nanocrystals exhibit ultra-high saturation magnetization, r1 and r2 relaxivities and high optical absorbance in the near-infrared region. Mesenchymal stem cells are able to internalize these nanoparticles, showing high negative-contrast enhancement in magnetic-resonance imaging (MRI). Preliminary in vivo experiments achieve long-lasting positive-contrast enhancement for vascular MRI in rabbits. These results point to the potential of using these nanocrystals for integrated diagnosis and therapeutic (photothermal-ablation) applications.

Abstract

Multiple receiver-coil data collection is an effective approach to reduce scan time. There are many parallel imaging techniques that reduce scan time using multiple receiver coils. One of these methods, partially parallel imaging with localized sensitivities (PILS), utilizes the localized sensitivity of each coil. The advantages of PILS over other parallel imaging methods include the simplicity of the algorithm, good signal-to-noise ratio (SNR) properties, and the fact that there is no additional complexity involved in applying the algorithm to arbitrary k-space trajectories. This PILS method can be further improved to provide truly parallel broadband imaging with the use of multiple-demodulation hardware. By customizing the demodulation based on each coil's location, the k-space sampling rate can be chosen based on each coil's localized sensitivity region along the readout direction. A simulated demodulation of data from 2D Fourier transform (FT) and spiral trajectories is shown to demonstrate the method's feasibility.

Abstract

Variable-density k-space sampling using a stack-of-spirals trajectory is proposed for ultra fast 3D imaging. Since most of the energy of an image is concentrated near the k-space origin, a variable-density k-space sampling method can be used to reduce the sampling density in the outer portion of k-space. This significantly reduces scan time while introducing only minor aliasing artifacts from the low-energy, high-spatial-frequency components. A stack-of-spirals trajectory allows control over the density variations in both the k(x)-k(y) plane and the k(z) direction while fast k-space coverage is provided by spiral trajectories in the k(x)-k(y) plane. A variable-density stack-of-spirals trajectory consists of variable-density spirals in each k(x)-k(y) plane that are located in varying density in the k(z) direction. Phantom experiments demonstrate that reasonable image quality is preserved with approximately half the scan time. This technique was then applied to first-pass perfusion imaging of the lower extremities which demands very rapid volume coverage. Using a variable-density stack-of-spirals trajectory, 3D images were acquired at a temporal resolution of 2.8 sec over a large volume with a 2.5 x 2.5 x 8 mm(3) spatial resolution. These images were used to resolve the time-course of muscle intensity following contrast injection.